Wntless functions in mature osteoblasts to regulate bone mass

Zhendong Zhong, Cassandra R. Zylstra-Diegel, Cassie A. Schumacher, Jacob J. Baker, April C. Carpenter, Sujata Rao, Wei Yao, Min Guan, Jill A. Helms, Nancy E Lane, Richard A. Lang, Bart O. Williams

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Recent genome-wide association studies of individuals of Asian and European descent have found that SNPs located within the genomic region (1p31.3) encoding the Wntless (Wls)/Gpr177 protein are associated significantly with reduced bone mineral density. Wls/Gpr177 is a newly identified chaperone protein that specifically escorts Wnt ligands for secretion. Given the strong functional association between the Wnt signaling pathways and bone development and homeostasis, we generated osteoblast- specific Wls-deficient (Ocn-Cre;Wls-flox) mice. Homozygous conditional knockout animals were born at a normal Mendelian frequency. Whole-body dual-energy X-ray absorptiometry scanning revealed that bone-mass accrual was significantly inhibited in homozygotes as early as 20 d of age. These homozygotes had spontaneous fractures and a high frequency of premature lethality at around 2 mo of age. Microcomputed tomography analysis and histomorphometric data revealed a dramatic reduction of both trabecular and cortical bone mass in homozygous mutants. Bone formation in homozygotes was severely impaired, but no obvious phenotypic change was observed in mice heterozygous for the conditional deletion. In vitro studies showed that Wls-deficient osteoblasts had a defect in differentiation and mineralization, with significant reductions in the expression of key osteoblast differentiation regulators. In summary, these results reveal a surprising and crucial role of osteoblast-secreted Wnt ligands in bone-mass accrual.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number33
DOIs
StatePublished - Aug 14 2012

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Osteoblasts
Homozygote
Bone and Bones
Ligands
X-Ray Microtomography
Spontaneous Fractures
Wnt Signaling Pathway
Genome-Wide Association Study
Bone Development
Photon Absorptiometry
Osteogenesis
Bone Density
Single Nucleotide Polymorphism
Proteins
Homeostasis

ASJC Scopus subject areas

  • General

Cite this

Zhong, Z., Zylstra-Diegel, C. R., Schumacher, C. A., Baker, J. J., Carpenter, A. C., Rao, S., ... Williams, B. O. (2012). Wntless functions in mature osteoblasts to regulate bone mass. Proceedings of the National Academy of Sciences of the United States of America, 109(33). https://doi.org/10.1073/pnas.1120407109

Wntless functions in mature osteoblasts to regulate bone mass. / Zhong, Zhendong; Zylstra-Diegel, Cassandra R.; Schumacher, Cassie A.; Baker, Jacob J.; Carpenter, April C.; Rao, Sujata; Yao, Wei; Guan, Min; Helms, Jill A.; Lane, Nancy E; Lang, Richard A.; Williams, Bart O.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 33, 14.08.2012.

Research output: Contribution to journalArticle

Zhong, Z, Zylstra-Diegel, CR, Schumacher, CA, Baker, JJ, Carpenter, AC, Rao, S, Yao, W, Guan, M, Helms, JA, Lane, NE, Lang, RA & Williams, BO 2012, 'Wntless functions in mature osteoblasts to regulate bone mass', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 33. https://doi.org/10.1073/pnas.1120407109
Zhong, Zhendong ; Zylstra-Diegel, Cassandra R. ; Schumacher, Cassie A. ; Baker, Jacob J. ; Carpenter, April C. ; Rao, Sujata ; Yao, Wei ; Guan, Min ; Helms, Jill A. ; Lane, Nancy E ; Lang, Richard A. ; Williams, Bart O. / Wntless functions in mature osteoblasts to regulate bone mass. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 33.
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